Alzheimer Disease, the major cause of dementia, is a progressive, degenerative disease characterized pathologically by extensive neuronal loss, deposits of amyloid .beta.-peptide in brain parenchyma and meningeal blood vessels and the presence of neurofibrillary tangles within neurons. Clinical diagnosis of Alzheimer Disease, is imprecise and no biochemical markers have been identified which can be used as a basis for a laboratory test to identify the disease. Currently diagnosis of the condition relies on the observations by a physician of the condition of the patient. Such methods of diagnosis are imprecise and prone to error depending on the experience of the physician and if the symptoms exhibited by the patient are typical for the condition. Such diagnostic procedures are susceptible to a high degree of variation depending on the physicians experience and interpretation of the results or the tests which are administered. Such subjective tests and observations are also difficult to apply by others as there is no objective standard which can be applied to the test nor the results obtained.
At present, it is estimated that Alzheimer Disease is correctly diagnosed only 60 to 80% of the time. Definitive diagnosis of the dementia can only be accurately preformed upon postmortem autopsy.
It is desirable to correctly diagnose the condition of the patient so that if the dementia falls within a group of treatable dementias, appropriate treatment may be initiated. If the dementia is Alzheimer Disease, it is important to correctly diagnose the disease so that the symptoms can be more accurately established and so that a treatment regime can be investigated. If patients are misdiagnosed a large percentage of the time proposed treatments for Alzheimer Disease, which may be effective with patients who actually do have Alzheimer Disease, may be discarded as ineffective because a large portion of the test group treated was not in fact suffering from this form of dementia but from another.
It is desirable that an objective test procedure is established for diagnosing Alzheimer Disease. Such a test is preferably non-invasive or minimally invasive so that the condition of the patient is not worsened by the test procedure. Typically, objective medical diagnoses rely on biochemical tests of extracellular body fluids, such as blood or urine. However, in the case of Alzheimer Disease no biochemical basis for the disease has been firmly established. It has been speculated that deposition of amyloid .beta.-peptide, resulting from the aberrant processing of amyloid peptide protein (APP), is the cause of Alzheimer Disease. This aberrant processing has been attributed in turn to abnormalities in the brain cell membrane, excess synthesis of amyloid precursor protein, neurotoxicity of excitatory amino acids including glutamate, or changes in the secondary messenger cascade. However, if these changes are in fact the cause or result of the changes that occur in Alzheimer Disease, none of them would be expected to produce a product which would be secreted into the extracellular body fluids for use as an Alzheimer Disease marker. Recently developed genetic markers determine the possible predisposition to develop Alzheimer Disease but are not effective in diagnosing an individual case of the disease.
Other analytical procedures rely on histological and biochemical analyses of biopsy samples. However, while these would be effective in diagnosing Alzheimer Disease they would have severe detrimental effect on the patient being diagnosed. Also biopsy samples may not accurately reflect the condition of the tissue while it was "alive" since degradation and biochemical anomalies often result after loss of oxygen and nutrients to brain tissue.
Non-invasive methods which are currently in use include magnetic resonance imaging (MRI) and magnetic resonance spectra (MRS). Since the gross anatomy of the brain is unaffected by Alzheimer Disease (except for atrophy), MRI is not expected to be a useful procedure. MRS has been used extensively to identify many chemicals in many different situation. .sup.31 P- and .sup.1 H-MRS have been used to identify the chemical composition of complex organic samples. Many studies have been performed in situ using .sup.31 P-MRS. Studies have used .sup.31 P-MRS to study Alzheimer Disease and have reported changes in the phospholipids in Alzheimer Disease. However, .sup.31 P-MRS is limited to chemicals which are phosphorylated. This includes only a small number of the chemicals in the body.
In U.S. Pat. No. 5,182,299 .sup.1 H-MRS was used as means for identifying concentrations of various biochemicals to diagnose osmotic disturbance in an animal and to monitor treatment of the condition. However, these studies relied on an in vitro analysis, which would be unsuitable for use in the diagnosis of Alzheimer Disease. Other studies have used .sup.1 H-MRS to study spectroscopic changes in the brain of patients with fulminating hepatic failure which showed low myo-inositol and high glutamate in grade I coma. None of the studies have identified a chemical correlation which can be associated with Alzheimer Disease. Additionally despite the potential of MRS for assessing in vivo metabolism, MRS has not yet acquired a significant place in clinical practice. The main reasons for this is the low sensitivity, low spacial resolution and low specificity due to tissue homogeneity. Another problem is that there is no way of measuring the size of the "sample" studied so that accurate concentrations of biochemicals in the sample can be calculated. This problem is generally considered to remain unsolved.
The potential of .sup.1 H-MRS to "observe" the biochemical concentrations in a tissue, without the need to take biopsy samples or any other type of sample makes it an ideal method for evaluating the conditions of dementia to accurately diagnose Alzheimer Disease. Therefore, it is desirable that a method is developed which will accurately determine the concentrations of chemicals in the brain to establish changes which are associated with Alzheimer Disease.